Hereditary spherocytosis with spectrin deficiency due to an unstable truncated beta spectrin
Hereditary spherocytosis with spectrin deficiency due to an unstable truncated beta spectrin
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DOI：
10.1182/blood.v87.6.2538.bloodjournal8762538
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发表时间：
1996-03-15
期刊：
影响因子：
20.3
通讯作者：
Palek, J
中科院分区：
文献类型：
--
作者：
Hassoun, H;Vassiliadis, JN;Palek, J
通过十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）进行红细胞膜蛋白分析，并通过放射免疫测定法或细胞荧光测定法进行直接定量，确定了遗传性球形红细胞增多症患者的四个不同亚群：单独血影蛋白缺乏症、血影蛋白和锚蛋白联合缺乏症、带3缺乏症和蛋白4.2缺乏症。关于第一组，文献中仅报道了β血影蛋白的一种突变。我们描述了一个血影蛋白变体的特点是截短的β链，并与遗传性球形红细胞增多症和孤立血影蛋白缺乏症。临床表型包括中度溶血性贫血与球形红细胞增多症和频繁的毛刺的红细胞，我们提出了这种突变蛋白的生化特性，并表明，它只构成12%的总血影蛋白的膜上。我们表明，蛋白质的截短是内含子17的供体共有剪接位点的位置+1（G --> A）处的单点突变导致缺失外显子16和17的异常β血影蛋白转录信息的结果。为了阐明膜上的截短蛋白和整体血影蛋白缺乏的量减少的基础，我们提供的证据表明，突变的基因被转录，但其mRNA比其正常对应的网织红细胞中的丰度较低;我们还表明，突变的蛋白质在红系祖细胞的细胞质中合成的量减少，似乎容易发生蛋白水解降解。这种突变血影蛋白强调了β血影蛋白分子在膜上α β血影蛋白异二聚体组装中所起的调节作用的重要性。(C)1996年，美国血液学会。
Red cell membrane protein analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and direct quantitation by radioimmunoassay or cytofluorometry defines four distinct subsets of patients with hereditary spherocytosis: Patients with isolated spectrin deficiency, combined spectrin and ankyrin deficiency, band 3 deficiency, and protein 4.2 deficiency. In regard to the first group, only one mutation of beta spectrin has been reported in the literature. We describe a spectrin variant characterized by a truncated beta chain, and associated with hereditary spherocytosis and isolated spectrin deficiency. The clinical phenotype consists of a moderate hemolytic anemia with spherocytosis and frequent spiculation of the red cells, We present the biochemical characteristics of this mutant protein and show that it constitutes only 12% of the total spectrin on the membrane. We show that the truncation of the protein is the result of a single point mutation at position +1 (G --> A) of the donor consensus splice site of intron 17 leading to an aberrant beta spectrin transcriptional message lacking exons 16 and 17. To elucidate the basis for the decreased amount of the truncated protein on the membrane and the overall spectrin deficiency, we provide evidence that the mutated gene is transcribed but its mRNA is less abundant than its normal counterpart in reticulocytes; we also show that the mutant protein is synthesized in decreased amounts in the cytoplasm of erythroid progenitor cells, and appears to be susceptible to proteolytic degradation. This mutant spectrin underscores the importance of the regulatory role played by the beta spectrin molecule in the assembly of alpha beta spectrin heterodimers on the membrane. (C) 1996 by The American Society of Hematology.